The immune response combines extraordinary specificity of recognition with extremely complex control mechanisms that govern its effector mechanisms. Childhood primary immunodeficiency disorders can be viewed as "experiments of nature" in which a discrete genetic defect affects the expression and/or the structure and function of essential lymphocyte proteins and results in immune dysfunctions. A molecular or genetic definition of primary immunodeficiencies is essential for accurate diagnosis and therapy of the disorders and for better understanding of normal immune functions. In this program project we propose to study a limited set of immunologic diseases, namely childhood T cell immunodeficiency diseases and atopic dermatitis. We will use recently acquired knowledge of T cell receptor structure and T cell activation to define the immunologic defects in these diseases. In parallel we will attempt to mimic those diseases in animal models by using the powerful tools of modern genetic engineering and DNA transfer into mouse embryos. The definition of T cell immunodeficiencies and immunological skin disorders in mice will permit a better understanding of these diseases. Once the objectives have been reached, the future directions of the program lead undoubtedly toward gene therapy via bone marrow transplant. As such, the model systems described in this proposal may have a wider impact on other immunological diseases (e.g., autoimmune diseases). The prospect for generating mutations in preselected genes of the immune system not only will permit the derivation of precise animal models of human hereditary diseases but also will mark the beginning of a systematic genetic dissection of the developmental processes that play a role in the ontogeny of the immune system.